title: 3'-Oxo-, amino-, thio- and sulfone-acetic acid modified thymidines: effect of increased acidity on ribonuclease A inhibition.
abstract: A family of 3'-functionalized thymidines carrying XCH₂COOH (X=O, NH, S, SO₂) groups has been designed as inhibitors of RNase A. This is because it is possible to manipulate the overall acidity of this new class of nucleic 'acids' by changing X from oxygen to the SO₂ group in the series. It is also expected that the acyclic nature of the XCH₂COOH group would provide enough flexibility to the -COOH group to have maximum interactions with the catalytic subsite P1 of RNase A. As the -SO₂CH₂COOH substituted derivative showed better potency partially because of the increased acidity of the -COOH group, the inhibitory properties of both 5'-substituted and 3',5'-disubstituted sulfone acetic acid modified thymidines were investigated. Two -SO₂CH₂COOH groups were incorporated with the expectation of targeting two phosphate binding sites simultaneously. Thus, 3',5'-dideoxy-3',5'-bis-S-[(carboxymethyl)sulfonyl]thymidine emerged as the best inhibitor in this series with a Ki value of 25 ± 2 μM.
authors.affiliation: Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India.
authors.forename: Dhrubajyoti
authors.initials: D
authors.lastname: Datta
authors.forename: Anirban
authors.initials: A
authors.lastname: Samanta
authors.forename: Swagata
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Tanmaya
authors.initials: T
authors.lastname: Pathak
mesh_terms: D000085:Acetates / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011485:Protein Binding; D012260:Ribonucleases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013936:Thymidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000085:Acetates; D004791:Enzyme Inhibitors; D012260:Ribonucleases; D013936:Thymidine